Cav-1 Ablation in Pancreatic Stellate Cells Promotes Pancreatic Cancer Growth through Nrf2-Induced shh Signaling

Oxid Med Cell Longev. 2020 Apr 20:2020:1868764. doi: 10.1155/2020/1868764. eCollection 2020.

Abstract

A more comprehensive understanding of the complexity of pancreatic cancer pathobiology, especially, and understanding of the role of the tumor microenvironment (TME) in disease progression should pave the way for therapies to improve patient response rates. Previous studies reported that caveolin-1 (Cav-1) has both tumor-promoting and tumor-suppressive functions. However, the function of Cav-1 in the pancreatic cancer microenvironment remains largely unexplored. Here, we show that coinjection of Cav-1-silenced pancreatic stellate cells (PSCs) with pancreatic cancer cells increased tumor growth. To comprehensively characterize paracrine communication between pancreatic cancer cells and PSCs, PSCs were cultured with pancreatic cancer cell conditioned medium (CM) containing cytokines. We reveal that Cav-1-silenced PSCs facilitated the growth of pancreatic cancer cells via enhanced paracrine shh/MMP2/bFGF/IL-6 signaling. Specifically, Cav-1-silenced PSCs exhibited increased shh expression, which heterotypically activated the shh signaling pathway in pancreatic cancer cells. Moreover, Cav-1-deficient PSCs accumulated ROS to enhance the shh pathway and angiogenesis in pancreatic cancer cells. In addition, overexpression of Nrf2 reversed the effects of Cav-1 knockdown on PSCs, increasing ROS production and enhancing paracrine shh/MMP2/bFGF/IL-6 signaling. Together, our findings show that stromal Cav-1 may mediate different mechanisms in the complex interaction between cancer cells and their microenvironment though Nrf2-induced shh signaling activation during pancreatic cancer progression.

MeSH terms

  • Animals
  • Caveolin 1 / deficiency
  • Caveolin 1 / metabolism*
  • Cell Line, Tumor
  • Hedgehog Proteins / metabolism*
  • Heterografts
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • NF-E2-Related Factor 2 / metabolism*
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Pancreatic Neoplasms / blood supply
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Pancreatic Stellate Cells / metabolism*
  • Pancreatic Stellate Cells / pathology

Substances

  • CAV1 protein, human
  • Caveolin 1
  • Hedgehog Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • SHH protein, human